Methods of treating medical conditions using peptides

ABSTRACT

The present invention provides peptides and pharmaceutical compositions thereof for appetite suppression and weight control. Preferred peptides are calcitonin analogs, preferably with specific amino acid changes to make the peptide more amylin-like.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.13/544,256, filed on Jul. 9, 2012, which is a continuation of U.S. Pat.No. 8,217,139, issued on Jul. 10, 2012, which is a continuation of U.S.Pat. No. 8,076,291, issued on Dec. 13, 2011, which claims the benefit ofand priority to U.S. Provisional Application Ser. No. 61/205,750, filedon Jan. 22, 2009, each of these applications is hereby incorporatedherein by reference in its entirety for the teachings therein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to peptides (and pharmaceuticalcompositions containing them) for suppressing appetite, and to their usefor treating and/or preventing overweight conditions or obesity insusceptible warm-blooded animals, including humans. In particular, theinvention relates to certain calcitonin analogs.

2. Background of the Related Art

Overweight condition or obesity is a well-known risk factor for manydiseases such as cardiovascular diseases, hypertension and diabetes.Moreover, personal appearance plays an important part in the overallwell-being of many people. An overweight condition may also reduce orlimit an individual's ability to participate in desired physicalactivities.

Common treatment and prevention programs include various diets(including food restriction diets), weight loss programs and exercise,which provide varying degrees of success that have not proven adequatefor many people. Numerous pharmaceutical compositions have been tried inthe prior art, sometimes with significant undesirable side effects.

Desirable reduction of food intake is made difficult by natural appetiteincrease which frequently accompanies the intake reduction. This resultsin significant patient noncompliance with regimens involving reductionof food intake. Thus, there is a need in the art for safe and effectiveappetite suppressants.

Calcitonins are known to suppress appetite, but are potent boneanti-resorptive agents. Their use as appetite suppressants is thereforelimited because of their effect on bone, which would not be desirablefor more general use in a weight control regimen.

SUMMARY OF THE INVENTION

It is accordingly an object of the present invention to providecalcitonin analogs which retain significant appetite suppressantactivity but which are less potent bone anti-resorptive agents thancalcitonin.

It is another object of the invention to provide novel peptides (andpharmaceutical compositions containing them) for use as appetitesuppressants.

It is another object of the invention to provide methods of suppressingappetite.

It is another object of the invention to provide methods of treatingand/or preventing an overweight condition and/or obesity.

In one embodiment, the present invention provides a peptide whose aminoacid sequence has at least 84 percent identity to the amino acidsequence of either salmon or eel calcitonin, wherein at least one aminoacid residue of said peptide is different from the corresponding aminoacid residues of both salmon and eel calcitonin and is identical to thecorresponding amino acid residue of human amylin.

In another embodiment, the present invention provides a peptide whoseamino acid sequence is at least 93 percent identical to SEQ ID NO:1,wherein said peptide is not eel or salmon calcitonin or human amylin.

In another embodiment, the present invention provides a peptide whoseamino acid sequence is at least 93 percent identical to SEQ ID NO:2,wherein said peptide is not eel or salmon calcitonin or human amylin.

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:1 wherein (i) residue 26may be either asparagine or aspartic acid, (ii) residue 29 may be eitherserine or alanine, and (iii) either residue 30 is not glycine or residue32 is not proline.

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:3.

In another embodiment the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:4.

In another embodiment the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:2 wherein: (i) residue 25may be either asparagine or aspartic acid, (ii) residue 28 may be eitherserine or alanine, and (iii) either residue 29 is not glycine or residue31 is not proline.

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:3, except that theleucine at position 16 is omitted (thus resulting in SEQ ID NO:5).

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:4, except that theleucine at position 16 is omitted (thus resulting in SEQ ID NO:6).

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:7.

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:8.

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:12.

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:13.

In another embodiment, the present invention provides a peptide havingthe amino acid sequence set forth in SEQ ID NO:14.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising any of the peptides of the invention describedherein together with a pharmaceutically acceptable excipient, diluent orcarrier.

In another embodiment, the present invention provides a method oftreating or preventing an overweight condition or obesity comprisingadministering to a patient in need of such prevention or treatment anamount of any of the peptides of the invention described herein (or apharmaceutical composition thereof) effective to suppress appetite.

In another embodiment, the present invention provides a method ofsuppressing appetite comprising administering to a patient in need ofsuch suppression an effective amount of any of the peptides of theinvention described herein (or a pharmaceutical composition thereof).

In another embodiment, the present invention provides a method oftreating diabetes comprising administering to a patient in need of suchtreatment a therapeutically effective amount of any of the peptides ofthe invention described herein (or a pharmaceutical compositionthereof).

In another embodiment, the present invention provides a method oftreating diabetes comprising administering to a patient in need of suchtreatment a therapeutically effective amount of any of the peptides ofthe invention described herein (or a pharmaceutical compositionthereof).

There are a number of art-recognized measures of normal range for bodyweight in view of a number of factors such as gender, age and height. Apatient in need of treatment or prevention regimens set forth hereininclude patients whose body weight exceeds recognized norms or who, dueto heredity, environmental factors or other recognized risk factor, areat higher risk than the general population of becoming overweight orobese. In accordance with the invention, it is contemplated that theinvention may be used to treat diabetes where weight control is anaspect of the treatment.

As used herein, “percent identity” refers to amino acid sequence withoutregard to whether a given amino acid is modified with an additionalsubstituent (other than an additional amino acid). For example cysteineis considered identical to acetylcysteine for this purpose. Likewise,for this purpose, a cysteine that has formed a disulfide bridge withanother cysteine would be considered identical to a cysteine that hasnot formed such a bridge. “Percent identity” also contemplatesdifferences in peptide size. For example, a 34-residue peptide that isotherwise identical to a 33-residue peptide (except for its oneadditional amino acid) is considered herein to be 97 percent identicalto the 33-residue peptide.

As those of skill in the art will appreciate, peptides having aplurality of cysteine residues frequently form a disulfide bridgebetween two such cysteine residues. All such peptides set forth hereinare defined as optionally including one or more such disulfide bridges.

The peptides known in the art as Davalintide and Pramlintide areexcluded from the scope of the invention.

Except where otherwise stated, the preferred dosage of the activecompounds of the invention is identical for both therapeutic andprophylactic purposes. Desired dosages are discussed in more detail,infra, and differ depending on mode of administration.

Except where otherwise noted or where apparent from context, dosagesherein refer to weight of active compounds uneffective by pharmaceuticalexcipients, diluents, carriers or other ingredients, although suchadditional ingredients are desirably included, as shown in the examplesherein. Any dosage form (capsule, tablet, injection or the like)commonly used in the pharmaceutical industry for delivery of peptideactive agents is appropriate for use herein, and the terms “excipient”,“diluent”, or “carrier” includes such non-active ingredients as aretypically included, together with active ingredients in such dosage formin the industry. A preferred oral dosage form is discussed in moredetail, infra, but is not to be considered the exclusive mode ofadministering the active agents of the invention.

Other features and advantages of the present invention will becomeapparent from the following non-limiting description of certainpreferred embodiments, which refers to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating data from a bioassay comparing cAMPresponse for a peptide of the invention, SEQ ID NO:3, versus recombinantsalmon calcitonin. Two replicate bioassay experiments were performedmeasuring the cAMP response with T47D cells. Each experiment comparedthree samples of SEQ ID NO:3 to a sample of rsCT.

FIG. 2 is a graph illustrating the effect on food consumption providedby SEQ ID NO:3 versus a placebo and two known appetite suppressants in aBeagle dog study. Average daily change in food consumption is shownfollowing administration of oral capsules containing various doses ofsCT, PYY or SEQ ID NO:3 given to beagle dogs for four to seven days.

FIG. 3 is a graph illustrating the effect on weight provided by SEQ IDNO:3 versus a placebo and two known appetite suppressants in a Beagledog study. Average daily change in weight is shown followingadministration of oral capsules containing various doses of sCT, PYY orSEQ ID NO:3 given to beagle dogs for four to seven days.

FIG. 4 is a graph illustrating calcitonin-like properties of threepeptides of the invention in comparison to salmon calcitonin in an assaythat measures binding to calcitonin receptors on T47D cells. The threepeptides of the invention are UGP269 (SEQ ID NO:12), UGP 271 (SEQ IDNO:13) and UGP281 (SEQ ID NO:14). The UGP269, UGP271 and UGP281exhibited less binding to sCT receptors than sCT.

FIG. 5 is a graph illustrating relative weight change by rats injecteddaily with the same dose of either a placebo, UGP269 (SEQ ID NO:12) orUGP 271 (SEQ ID NO:13), at 7 and 14 days after commencement of theinjection regimen. Rats injected with UGP269 showed less weight gainover two weeks than those injected with placebo. Rats injected with thesame dose of UGP271 showed no weight gain. UGP271 contained nearly thesame sequence of amino acids as UGP269 except for the replacement ofthree amino acids at positions 26, 27 and 29.

FIG. 6 is a graph illustrating relative weight change by rats injecteddaily with the same dose of either a placebo, salmon calcitonin, UGP 271(SEQ ID NO:13) or UGP 281 (SEQ ID NO:14) at 7 and 14 days aftercommencement of the injection regimen. FIG. 1 is a graph illustratingdata from a bioassay comparing cAMP response for a peptide of theinvention, SEQ ID NO:3, versus recombinant salmon calcitonin. Ratsinjected intramuscularly with sCT or UGP281 exhibited significant weightloss when injected for two weeks; whereas, rats injected with the samedose of UGP271 exhibited modest weight loss. UGP281 and UGP271 hadidentical amino acid sequences except that UGP281 was acylated at theN-terminus with acetate.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

Preferred peptides of the invention have significant amino acid identityto either salmon or eel calcitonin. Preferably, there is at least 84%identity, and in some embodiments as much as 87%, 90%, 93% or 96%identity to either eel or salmon calcitonin. Preferably, at least oneamino acid is modified, relative to both salmon and eel calcitonin, forpurposes of decreasing the effect of a peptide of the invention on bone(relative to salmon or eel calcitonin's effect on bone).

In some embodiments, the leucine at position 16 of salmon and eelcalcitonin is deleted such that an 31-amino acid peptide results. It isexpected that this deletion is likely to desirably decrease theresulting peptide's ability to bind kidney, and osteoclasts relative tonatural salmon or eel calcitonin.

While peptides of the invention may exist in free acid form, it ispreferred that the C-terminal amino acid be amidated. Applicants expectthat such amidation may contribute to the effectiveness and/orbioavailability of the peptide.

In preferred embodiments, peptides of the invention, whether or not theyinclude the leucine-16 of salmon or eel calcitonin, may have from 1 to 5positions where their amino acid differs from the corresponding aminoacid of both salmon and eel calcitonin. As used herein, the phrase“corresponding amino acid of salmon or eel calcitonin” means the aminoacid residue of either salmon or eel calcitonin having the same aminoacid position number (relative to its amino terminus) as is beingdiscussed for peptides of the invention where the phrase is used, EXCEPTwhere the phrase is used in embodiments where leucine-16 is deleted, inwhich case the “corresponding” amino acid number of salmon or eelcalcitonin is one position higher than any position number over 15 inthe peptide of the invention.

Preferred positions where the peptide of the invention differs from botheel and salmon calcitonin, for example, are positions 8, 11, 27, 30 and32. In a peptide of the invention in which leucine-16 has been deleted,relative to natural salmon or eel calcitonin, the foregoing preferredpositions of change are positions 8, 11, 26, 29 and/or 31 (correspondingto positions 8, 11, 27, 30 and/or 32 of natural salmon or eelcalcitonin). Changes at one or more of these preferred positions, or atother positions, are believed to decrease the effect the peptide wouldotherwise have on bone, which effect is not desirable in connection withappetite suppression and/or treatment of overweight conditions orobesity.

Without intending to be bound by theory, it is believed that theappetite suppression provided by the peptides of the invention ismediated by binding of the peptides of the invention to the amylinreceptor. Thus, in preferred embodiments, the peptides of the inventionare desired to be superagonists of the amylin receptor while havingdiminished binding to the calcitonin receptor. In preferred embodiments,positions where the peptides of the invention differ from thecorresponding positions of salmon and/or eel calcitonin preferablyutilize the corresponding amino acid of human amylin at the position inquestion. The phrase “corresponding amino acid of human amylin” as usedherein means the amino acid number of human amylin that is the same asthe amino acid number of the peptide of the invention being discussed,EXCEPT when the amino acid residue number of the peptide of theinvention being discussed is higher than 24, in which case the“corresponding” amino acid residue number of human amylin is 5 higherthan the amino acid number of the peptide of the invention. For example,amino acid 24 of the invention corresponds to amino acid number 24 ofhuman amylin, while amino acid 25 of the invention corresponds to aminoacid number 30 of human amylin. In embodiments of the invention whereinleucine-16 is omitted, the “corresponding numbers between the inventionand human amylin are identical through the first 15 residues, differ byone with residues 16-23 (corresponding to residue 17-24 of humanamylin), and differ by six beginning with residue number 24 of thepeptide of the invention (which “corresponds to residue 30 of humanamylin).

One peptide of the invention, the peptide of SEQ ID NO:3, has asparagineat position 30 and tyrosine at position 32 (corresponding to amylin'sasparagine-35 and tyrosine-37) instead of the amino acid residues thateel or salmon calcitonin have at positions 30 and 32. Preferred peptideSEQ ID NO:3 otherwise has the same amino acid sequence as does salmoncalcitonin at all positions other than positions 30 and 32 where thepeptide has been made more amylin-like. In accordance with anotherpreference of the invention, SEQ ID NO:3 is amidated at tyrosine-32.

Pramlintide, commercially available under the trademark SYMLIN, is ananalog of amylin which differs from amylin in ways that resist formationof aggregates (which can be a problem with amylin). Accordingly, thepresent invention contemplates that pramlintide might be utilized in thesame way that amylin is utilized herein. Likewise, elcatonin (an analogof eel calcitonin) might be utilized in the same way that eel calcitoninis utilized herein.

Another peptide of the invention is set forth at SEQ ID NO:4 which issimilar to SEQ ID NO:3 except that it contains valine at position 27.Valine-27 makes SEQ ID NO:4 more amylin-like (i.e., corresponds tovaline-32 in human amylin). Valine-27 also makes SEQ ID NO:4 moreclosely resemble eel calcitonin (as opposed to salmon calcitonin) whicheel calcitonin also has valine at position 27.

In another embodiment, a peptide of the invention may be identical toSEQ ID NO:3 and SEQ ID NO:4, but missing leucine-16.

In another embodiment, a peptide of the invention may have the aminoacid sequence set forth at SEQ ID NO:7 or SEQ ID NO:8

For ease of comparison, the amino acid sequences of natural salmon andeel calcitonin are set forth as SEQ ID NO:9 or SEQ ID NO:10,respectively. The amino acid sequence for human amylin is set forth atSEQ ID NO:11.

In some embodiments, the N-terminal side of the peptides discussed suprais modified to reduce the positive charge of the first amino acid. Forexample, an acetyl or propionyl group may be substituted on cysteine-1.As illustrated by FIG. 6, improved effectiveness is achieved by such anacetyl substitution. Alternative ways of reducing positive chargeinclude but are not limited to polyethylene glycol-based PEGylation, orthe addition of another amino acid such as glutamic acid or asparticacid at the N-terminus. Alternatively, adding other amino acids to theN-terminus of peptides discussed supra may desirably reduce signaltransduction by the calcitonin receptor. Such additional amino acidsinclude but are not limited to lysine, glycine, formylglycine, leucine,alanine, acetyl alanine, and dialanyl.

In some embodiments, peptides discussed supra may be further modified bysubstituting, for a given amino acid residue, the corresponding aminoacid of human amylin.

Recombinant production of peptides of the invention is believed to bemore cost effective than other techniques known in the art, althoughthese other techniques may also be used. Preferably, the peptides of theinvention are amidated at their C-terminus, although free acid forms arealso contemplated. A preferred technique for manufacturing amidatedversions of the peptides of the invention is to react precursors (havingglycine in place of the C-terminal amino group of the desired amidatedproduct) in the presence of peptidylglycine alpha-amidatingmonooxygenase in accordance with known techniqes wherein the precursorsare converted to amidated products in reactions described, for example,in U.S. Pat. No. 4,708,934 and European Patent Publication Nos. 0 308067 and 0 382 403. Recombinant production is preferred for both theprecursor and the enzyme that catalyzes the conversion of the precursorto salmon calcitonin. Such recombinant production is discussed inBiotechnology, Vol. 11 (1993) pp. 64-70, which further describes aconversion of a precursor to an amidated product. The recombinantproduct reported there is identical to natural salmon calcitonin, and tosalmon calcitonin produced using solution and solid phase chemicalpeptide synthesis. Production of amidated products may also beaccomplished using the process and amidating enzyme set forth byConsalvo, et al in U.S. Patent Publication No. 2006/0127995; Miller etal, U.S. Patent Publication No. 2006/0292672; Ray et al, 2002, ProteinExpression and Purification, 26:249-259; and Mehta, 2004, Biopharm.International, July, pp. 44-46.

The production of the preferred amidated peptides may proceed, forexample, by producing glycine-extended precursor in E. coli as a solublefusion protein with glutathione-S-transferase, or by direct expressionof the precursor in accordance with the technique described in U.S. Pat.No. 6,103,495. Such a glycine extended precursor has a molecularstructure that is identical to the desired amidated product except atthe C-terminus (where the product terminates —X—NH₂, while the precursorterminates —X-gly, X being the C-terminal amino acid residue of theproduct). An alpha-amidating enzyme described in the publications abovecatalyzes conversion of precursors to product. That enzyme is preferablyrecombinantly produced, for example, in Chinese Hamster Ovary (CHO)cells), as described in the Biotechnology and Biopharm. articles citedabove.

Free acid forms of peptide active agents of the invention may beproduced in like manner, except without including a C-terminal glycineon the “precursor”, which precursor is instead the final peptide productand does not require the amidation step.

Treatment of Patients

It is preferred that peptides of the invention be administered atadequate dosage to maintain serum levels of the peptide in patientsbetween 5 and 500 picograms per milliliter, preferably between 10 and250 picograms per milliliter. The serum levels may be measured byradioimmunoassay techniques known in the art. The attending physicianmay monitor patient response, and may then alter the dosage somewhat toaccount for individual patient metabolism and response.

While other delivery methods may be used, a peptide of the invention ispreferably formulated for oral delivery in a manner known in the art,for example as set forth in U.S. Pat. No. 6,086,018, or U.S. PatentPublication No. 2009/0317462. One preferred oral dosage form inaccordance with the invention is set forth in Table 1 below:

TABLE 1 COMPONENTS OF SOLID DOSAGE FORMULATION ACTIVE AGENT OR EXCIPIENTFUNCTION Peptide of SEQ ID NO: 3 Active agent for appetite suppressionCoated Citric Acid Protease Inhibitor Lauroylcarnitine AbsorptionEnhancer Nonionic Polymer Subcoat Eudragit L30D-55 Enteric Coat

The bioavailability achievable in an oral dosage form of this type isexpected to be adequate to achieve the above preferred blood levelswhile using only 100-2000 micrograms of active peptide (in this exampleSEQ ID NO:3) per dosage form, preferably 200-800 micrograms. When oralformulations of this type and concentration of active ingredient areused, dosages of between 200 and 4000 micrograms per day of activepeptide (exclusive of weight of all other ingredients), and preferablybetween 400 and 1600 micrograms per day, is likely to achieve targetblood levels.

These amounts may be provided by either a single daily dosage ormultiple dosages. Regardless of the active agent being administered, itis preferred that a single dosage form (for example, a single capsule ortablet) be used at each administration because a single capsule ortablet best provides simultaneous release of the peptide active agent,pH-lowering agent and absorption enhancers. This is highly desirablebecause the acid is best able to reduce undesirable proteolytic attackon the peptide active agent when the acid is released in close timeproximity to release of the active agent.

Near simultaneous release is best achieved by administering allcomponents of the invention as a single pill or capsule. However, theinvention also includes, for example, dividing the required amount ofthe active ingredient among two or more tablets or capsules which may beadministered together such that they together provide the necessaryamount of all ingredients. “Pharmaceutical composition,” as used hereinincludes but is not limited to a complete dosage appropriate to aparticular administration to a patient regardless of whether one or moretablets or capsules (or other dosage forms) are recommended at a givenadministration.

Peptides in accordance with the invention may also be delivered by othercommon techniques in the industry with normal dosage variations betweenmodes of administration For example, a dosage range between 5 and 100micrograms per day, (preferably between 10 and 50 micrograms per day,and most preferably between 15 and 35 micrograms per day), is preferredwhen administered by injection.

In a pharmaceutical composition for injection, the peptide active agentof the invention is preferably present in a concentration between 10micrograms/mL and 100 micrograms/mL.

Without intending to be bound by theory, the mechanism of action isbelieved to involve leptin. In some embodiments, leptin may be added tothe pharmaceutical composition of the invention, or separately provided.

Efficacy Data

To test whether amino acid substitutions of the invention convertedsalmon calcitonin to an analog with less binding affinity to thecalcitonin receptor (or otherwise less able to undesirably activatecalcitonin receptors, the peptide whose amino acid sequence is set forthin SEQ ID NO: 3 was subjected to a bioassay comparing its cAMP response(an indicator of calcitonin receptor activation) to that of salmoncalcitonin. As shown in FIG. 1, the data suggest that a calcitoninanalog of the invention (SEQ ID NO: 3) is desirably less potent whenbinding to the calcitonin receptor than is natural salmon calcitonin.

The effect of peptide SEQ ID NO: 3 on food intake was investigated in aplacebo controlled crossover study with Beagle dogs. Peptide SEQ ID NO:3, as well as salmon calcitonin (sCT) and PYY(3-36)NH₂ were formulatedin enteric-coated capsules for oral delivery. The capsules alsocontained excipients that inhibit proteases and enhance the absorptionof peptides. Placebo capsules contained the same excipients without thepeptide. Food and water intake, as well as the weight of the dogs wasmonitored daily before, during, and after the dosing period. Dogs wereallowed access to a known amount of food for an 8 hour period every day,and water was provided ad libitum. As shown in FIG. 2, at equivalentdoses, SEQ ID NO: 3 and sCT significantly decreased food intakethroughout the week of dosing, whereas PYY exhibited a lesser effect.The food intake of dogs given a placebo remained unchanged.

As shown in FIG. 3, dogs given SEQ ID NO: 3 and sCT showed a small butsignificant reduction in weight during the dosing period, whereas dogsreceiving the same dose of PYY showed very little change (0.05% per day)in weight. Dogs given placebo capsules exhibited a slight weightincrease.

Finally, while water intake was also reduced during the dosing period,it was by a smaller amount than the reduction in food intake. Both foodand water intake returned to pre-dose levels during the one week washoutperiod following dosing.

FIGS. 1-3 provide evidence that SEQ ID NO: 3 offers the potential ofaffecting feeding behavior by reducing food consumption, with a potencythat is comparable to that of the bone anti-resorptive peptide sCT.

Likewise, FIG. 4 illustrates that UGP269 (SEQ ID NO:12), UGP 271 (SEQ IDNO:13) and UGP281 (SEQ ID NO:14) has less binding affinity for thecalcitonin receptor than does salmon calcitonin.

FIGS. 5 and 6 illustrate good effectiveness in weight control by UGP269(SEQ ID NO:12), UGP 271 (SEQ ID NO:13) and UGP281 (SEQ ID NO:14). FIG. 6provides evidence of substantial enhancement of efficacy by the acetylgroup on cysteine-1 of UGP281 (SEQ ID NO:14).

Although the present invention has been described in relation toparticular embodiments thereof, many other variations and modificationsand other uses will become apparent to those skilled in the art. Thepresent invention therefore is not limited by the specific disclosureherein, but only by the claims.

What is claimed is:
 1. A method of treating an overweight condition in apatient comprising: administering a 32 amino acid peptide to thepatient, wherein the amino acid sequence of the peptide is at least 93percent identical to SEQ ID NO: 1, wherein positions 2-32 of the peptideare identical to positions 2-32 of SEQ ID NO: 1, and wherein position 1of the peptide is cysteine that has been modified with a group selectedfrom one of a succinyl group, an acetyl group or a propionyl group. 2.The method of claim 1 wherein position 26 of the peptide is Asparagine.3. The method of claim 1 wherein position 27 of the peptide isThreonine.
 4. The method of claim 1 wherein position 29 of the peptideis Serine.
 5. The method of claim 1 wherein position 30 of the peptideis Glycine.
 6. The method of claim 1 wherein the amino acid at position32 of the peptide is amidated.
 7. The method of claim 1 wherein position32 of the peptide is proline.
 8. The method of claim 1 wherein thepeptide is a component of a solid oral dosage form, and wherein thesolid oral dosage form is selected from one of a capsule or a tablet. 9.The method of claim 1 wherein the peptide is a component of apharmaceutical composition for injection.
 10. The method of claim 1wherein administering occurs multiple times over a period of time.
 11. Amethod of treating diabetes in a patient comprising: administering a 32amino acid peptide to the patient, wherein the amino acid sequence ofthe peptide is at least 93 percent identical to SEQ ID NO: 1, whereinpositions 2-32 of the peptide are identical to positions 2-32 of SEQ IDNO: 1, and wherein position 1 of the peptide is cysteine that has beenmodified with a group selected from one of a succinyl group, an acetylgroup or a propionyl group.
 12. The method of claim 11 wherein position26 of the peptide is Asparagine.
 13. The method of claim 11 whereinposition 27 of the peptide is Threonine.
 14. The method of claim 11wherein position 29 of the peptide is Serine.
 15. The method of claim 11wherein position 30 of the peptide is Glycine.
 16. The method of claim11 wherein the amino acid at position 32 of the peptide is amidated. 17.The method of claim 11 wherein position 32 of the peptide is proline.18. The method of claim 11 wherein the peptide is a component of a solidoral dosage form, and wherein the solid oral dosage form is selectedfrom one of a capsule or a tablet.
 19. The method of claim 11 whereinthe peptide is a component of a pharmaceutical composition forinjection.
 20. The method of claim 11 wherein administering occursmultiple times over a period of time.